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This review synthesizes current evidence on personalized obesity management, dietary interventions, and advanced pharmacotherapies aligned with the new 2025 Lancet Commission framework. A comprehensive narrative review was conducted across major biomedical databases to evaluate the efficacy, safety, and mechanisms of metabolic interventions, focusing on phenotype-specific dietary matching, bioactive compounds, and modern multi-receptor glucagon-like peptide-1 (GLP-1)-based therapies across preclinical and clinical intervention tiers in adult and pediatric populations. While specific nutraceutical extracts display promising secondary metabolic benefits, their overall weight-loss efficacy remains modest due to variable clinical data and limited sample sizes. Conversely, high-potency anti-obesity medications demonstrate unprecedented weight-reduction efficacy, with semaglutide 2.4 mg and tirzepatide yielding mean body weight losses of ~14.9% and ~20.9%, respectively. Furthermore, landmark outcome data from the SELECT trial confirms that semaglutide 2.4 mg achieves a significant 20% relative risk reduction in major adverse cardiovascular events (MACE), independent of baseline glycemic status or heart failure. However, clinical extension data reveal rapid weight rebound upon drug cessation, highlighting that obesity requires continuous, long-term therapeutic strategies. Effective obesity care demands an operational shift from traditional, one-size-fits-all treatments to personalized, multi-tiered strategies. Combining phenotype-specific lifestyle modifications with potent, long-term multi-hormonal pharmacotherapies or metabolic surgery optimizes long-term therapeutic durability, systemic metabolic health, and sustained cardioprotection.<\/jats:p>","DOI":"10.3390\/nu18142317","type":"journal-article","created":{"date-parts":[[2026,7,16]],"date-time":"2026-07-16T01:05:07Z","timestamp":1784163907000},"page":"2317","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Understanding Obesity as a Multisystem Disease: Advancing Research, Redefining Diagnostic Criteria, and Establishing Modern Therapeutic Approaches"],"prefix":"10.3390","volume":"18","author":[{"given":"Hala","family":"Abdallah","sequence":"first","affiliation":[{"name":"Internal Medicine Clinica Medica \u201cA. 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